Discovery of piperazic acid peptide deformylase inhibitors with in vivo activity for respiratory tract and skin infections.
Bioorg Med Chem Lett
; 29(16): 2410-2414, 2019 08 15.
Article
em En
| MEDLINE
| ID: mdl-31160176
ABSTRACT
The discovery of a novel series of peptide deformylase inhibitors incorporating a piperazic acid amino acid found in nature is described. These compounds demonstrated potent in vitro enzymatic potency and antimicrobial activity. Crystal structure analysis revealed the piperazic acid optimized a key contact with the PDF protein that accounted for the increased enzymatic potency of these compounds. We describe lead optimization of the P3' region of the series that resulted in a compound with good potency against three target organisms. One molecule showed in vivo efficacy in a rat respiratory infection model but ultimately did not meet candidate progression criteria.
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Base de dados:
MEDLINE
Assunto principal:
Piridazinas
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Infecções Respiratórias
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Dermatopatias Infecciosas
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Inibidores Enzimáticos
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Amidoidrolases
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Antibacterianos
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article